Genistein affects ERβ- but not ERα-dependent gene expression in the hypothalamus

Isoflavone phytoestrogens are growing increasingly popular because of their reported cardiovascular and anticarcino-genic properties, but the effects of these compounds in the brain are largely unknown. In a previous study, we found that an isoflavone supplement, containing a mixture of soy phytoestrogens, inhibited estrogen-dependent female sexual behavior and was antiestrogenic for both ERalpha- and ERbeta-dependent gene expression in the hypothalamus. Here we examined the impact of the soy isoflavone genistein, a major component of the supplement, on estrogen-dependent female sexual behavior and ERalpha- and ERbeta-dependent gene expression in the rat brain. Genistein, at a dietary concentration of 100 or 500 ppm had no effect on lordosis behavior in rats. However, at 500 ppm genistein had differential activity through ERalpha and ERbeta in the hypothalamus. Genistein had no effect, in either the presence or absence of 17beta-E2, on oxytocin receptor density in the ventromedial nucleus of the hypothalamus, an estrogen-DEPENDENT action thought to be regulated via ERalpha. However, genistein increased ERbeta mRNA expression in the paraventricular nucleus of the hypothalamus by 24%, whereas 17beta-E2 decreased ERbeta mRNA expression by 26%, a process likely mediated by ERbeta itself. These results suggest that at this dose, genistein has antiestrogenic action through ERbeta in the paraventricular nucleus but negligible activity through ERalpha in the brain.